In industrialized countries about one third of the adult population smokes cigarettes, resulting in a major avoidable cause of morbidity and mortality. Smoking is a contributory or causative factor in a number of diseases including respiratory diseases such as emphysema, chronic bronchitis, lung infections, and lung cancer; cardiovascular disease; gastric and duodenal ulcers; and cancer of the lung, oral cavity, larynx and oesophagus.
Most regular smokers become addicted to, or dependent upon, the pharmacological effects of nicotine in tobacco smoke. Nicotine is rapidly absorbed across the blood brain barrier and exerts a direct action on nicotine receptors in the spinal cord, autonomic ganglia and adrenal medulla. For more detailed information on the pharmacologic effects of nicotine see, for example, Oates and Wood, New Eng. J. Med. 319:1318, 1988. Nicotine itself has been implicated as a contributory factor in coronary heart diseases, peripheral vascular disease and hypertension.
Although nicotine is responsible for the addictive nature of cigarette smoking, most of the harmful health effects of smoking are attributable to other constituents in cigarette smoke (The Lancet, 337:1191, May 18, 1991). The combustion of tobacco in cigarettes results in the production of up to 4,000 compounds and the inhalation of such unwanted by-products as tar, combustion gases and a range of carcinogens. Nicotine may be nitrosated to form highly carcinogenic tobacco-specific N-nitrosamines in tobacco smoke, or in the cured smokeless tobacco for use as chewing tobacco or snuff. It is an unfortunate feature of cigarette smoking that the negative consequences of nicotine addiction are largely manifested by the inhalation of toxic and carcinogenic materials generated by the combustion of tobacco.
Addiction to smoking is based upon a pharmacological dependence on nicotine, an addiction comparable to that arising from the use of heroin. There are a number of acute symptoms of smoking cessation relating to nicotine withdrawal including irritability, anxiety, insomnia and a craving for nicotine. The addictive nature of nicotine poses a major obstacle to those who wish to quit smoking and a number of approaches have been developed to aid individuals in their efforts to stop smoking. The more successful of these involve therapy with nicotine substitutes such as chewing gum, nicotine patches, nicotine nasal sprays, nicotine vapour and the like. However, as discussed in more detail below, these approaches have met with limited user acceptance and limited success. In addition, there are individuals who are unable to stop despite repeated attempts, due to the addictive nature of nicotine. These individuals could benefit from a product which fulfilled their craving for nicotine, but did not have the same detrimental health consequences as cigarettes.
Smoking is a uniquely effective form of systemic drug administration. As nicotine enters the circulation via the pulmonary circulation, it is speedily transported to the brain. Smokers achieve a rapid peak in nicotine levels in the blood within one or two minutes after finishing a cigarette. Nicotine substitutes generally contain nicotine in solid form, in a vapour or in solution. As nicotine is a base, these preparations are alkaline. The alkalinity of nicotine substitutes is frequently increased, for example to Ph 10 because at high Ph nicotine is not ionized and ionization is know to impede the passage of nicotine across biological membranes (Burch et al., Am. Rev. Respir. Dis. 1989, 140:955).
With respect to nicotine gum, it is known that nicotine, even at an alkaline Ph, is absorbed slowly across the mucous membranes of the oral cavity, so absorption by this route does not produce the very rapid increase in nicotine levels associated with cigarette smoking. Therefore, buccal absorption has proved to have limited use in simulating the effects of cigarette smoking and lessening the adverse symptoms of nicotine withdrawal. Lower nicotine levels are achieved from chewing nicotine gum compared to smoking cigarettes and the gum has been associated with gastro intestinal side effects, hiccups, mouth ulcers and sore throat. The amount of nicotine absorbed is also highly variable and is dependent upon the chewing and swallowing actions of the user over a prolonged period of time.
Nicotine patches are associated with skin irritation at the application site. Both nicotine gum and dermal patches result in slow absorption of nicotine which is frequently not effective in satisfying the patient's craving for cigarettes. This may be one of the reasons for the lack of success of these forms of therapy in weaning subjects from smoking.
Self-propelled aerosols (also know as "pressurized aerosols") which contain nicotine in solution have also been proposed as cigarette substitutes. An example is the self-propelled aerosol formulation of Jacobs in U.S. Pat. No. 4,635,651. Such formulations are packaged in pressurized metered dose delivery systems. As shown in Jacobs, these delivery systems contain a water based aerosol formulation and a propellant such as pressurized freon which are stored in a pressurized storage container. When the device is used by an individual, the user aims the delivery system into their mouth. The user then inhales while causing a premetered dose of aerosol to be forced from the storage container and expelled at high speed into the user's mouth.
There are a number of problems with such pressurized aerosols. Pressurized aerosols require coordination on the part of the user who ideally should inhale at exactly the same time as the device is actuated in order to deliver the drug into the lungs. Frequently pressurized aerosols are inhaled near the end of respiratory intake resulting in poor delivery to the distal portions of the lungs. For the foregoing reason, the dose of nicotine administered by using pressurized aerosols can not be accurately controlled.
Failure to coordinate actuation of an aerosol inhaler and inhalation results in deposition of the aerosol in the oral cavities and upper respiratory tracts. In addition, even if the user properly aims the delivery device and coordinates the inhalation, the speed with which the aerosol is expelled from the device and enters the mouth causes much of the aerosol to impact on the throat and upper airways of the user. For example, Jacobs in U.S. Pat. No. 4,635,651 expelled particles of about 40 .mu.m. These particles would comprise agglomerations of particles and solvents. As the particles travel from the inhaler into the airway of the user, the particles would break up into smaller particles and some of the solvent would operate. However, even these smaller particles would still be at least about 10 .mu.m as they travelled through the mouth of the user and would accordingly impact on the throat and upper airways of the user. Aerosols utilize nicotine which is in solution. Since nicotine in solution has an alkaline pH which irritates the throat and upper airways, aerosols have poor acceptance by smokers (Burch et al., 1989, Am. Rev. Respir. Dis. 140:955).
Further, it is problematic to produce particles of an optimal size for absorption in the alveoli with a self-propelled aerosol. Jacobs in U.S. Pat. No. 4,635,651 included a solid particulate component of defined size into a pressurized aerosol formulation of an inhalable nicotine solution.